Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use

ABSTRACT

The invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally sitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent.

RELATED APPLICATIONS

This application claims priority under 35 USC § 119 to U.S. ProvisionalApplication No. 60/387,433 filed Jun. 11, 2002.

FIELD OF THE INVENTION

The invention describes novel nitrosated and/or nitrosylatedcyclooxygenase 2 (COX-2) selective inhibitors and novel compositionscomprising at least one nitrosated and/or nitrosylated cyclooxygenase 2(COX-2) selective inhibitor, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, stimulates endogenoussynthesis of nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase, and/or at least one therapeutic agent. The invention alsoprovides novel compositions comprising at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide,elevates endogenous levels of endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase and/or at least one therapeutic agent. Theinvention also provides novel kits comprising at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, optionally, at least one nitric oxide donor and/or at least onetherapeutic agent. The invention also provides methods for treatinginflammation, pain and fever; for treating and/or improving thegastrointestinal properties of COX-2 selective inhibitors; forfacilitating wound healing; for treating and/or preventing renal and/orrespiratory toxicities; for treating and/or preventing other disordersresulting from elevated levels of cyclooxygenase-2; and for improvingthe cardiovascular profile of COX-2 selective inhibitors. The novelnitrosated cyclooxygenase 2 selective inhibitors of the invention arepreferably nitrosated derivatives of2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used forthe treatment of pain, inflammation, and acute and chronic inflammatorydisorders such as osteoarthritis and rheumatoid arthritis. Thesecompounds inhibit the activity of the enzyme cyclooxygenase (COX), alsoknown as prostaglandin G/H synthase, which is the enzyme that convertsarachidonic acid into prostanoids. The NSAIDs also inhibit theproduction of other prostaglandins, especially prostaglandin G₂,prostaglandin H₂ and prostaglandin E₂, thereby reducing theprostaglandin-induced pain and swelling associated with the inflammationprocess. The chronic use of NSAIDs has been associated with adverseeffects, such as gastrointestinal ulceration and renal toxicity. Theundesirable side effects are also due to the inhibition of prostaglandinin the affected organ.

Recently two isoforms of cyclooxygenase, encoded by two distinct genes(Kujubu et al, J. Biol. Chem., 266, 12866–12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective. Recently compounds that are COX-2 selective inhibitors havebeen developed and marketed. These COX-2 selective inhibitors have thedesired therapeutic profile of an antiinflammatory drug without theadverse effects commonly associated with the inhibition of COX-1.However, these compounds can result in dyspepsia and can causegastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).Additionally the COX-2 selective inhibitors can increase the risk ofcardiovascular events in a patient (Mukherjee et al., JAMA 286(8)954–959 (2001)); Hennan et al., Circulation, 104:820–825 (2001)).

There is still a need in the art for novel COX-2 selective inhibitorcompounds that have gastroprotective properties, facilitate woundhealing, decreased renal and/or respiratory toxicity and dyspepsia,improved cardiovascular profile and that can be used at low dosages. Theinvention is directed to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The invention provides novel nitrosated and/or nitrosylated derivativesof COX-2 selective inhibitors, or a pharmaceutically acceptable saltthereof. These compounds are potent analgesics, have antiinflammatoryproperties and have an unexpected potential for facilitating woundhealing. The novel compounds also have unexpected properties in thetreatment and/or prevention of renal and/or respiratory toxicity and forimproving the cardiovascular profile of COX-2 selective inhibitors. TheCOX-2 selective inhibitor, or a pharmaceutically acceptable saltthereof, can be nitrosated and/or nitrosylated through one or moresites, such as oxygen (hydroxyl condensation), sulfur (sulfhydrylcondensation) and/or nitrogen. The invention also provides compositionscomprising the novel compounds described herein in a pharmaceuticallyacceptable carrier.

The invention is also based on the discovery that administering at leastone parent COX-2 selective inhibitor, and, optionally, at least onenitric oxide donor reduces the gastrointestinal distress induced byCOX-2 selective inhibitors. Nitric oxide donors include, for example,S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM5185, SPM 5186 and analogues thereof, and substrates of the variousisozymes of nitric oxide synthase. Thus, another aspect of the inventionprovides compositions comprising at least one parent COX-2 selectiveinhibitor and at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO−), or as the neutral species, nitric oxide (NO•), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The invention also provides forsuch compositions in a pharmaceutically acceptable carrier.

Yet another aspect of the invention provides compositions comprising atleast one COX-2 selective inhibitor, that is optionally substituted withat least one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO•), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase, and/or, optionally, at least one therapeutic agent, includingbut not limited to, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMG CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like. The invention also provides for suchcompositions in a pharmaceutically acceptable carrier.

Yet another aspect of the present invention provides methods fortreating and/or preventing inflammation, pain and fever; for treatingand/or improving gastrointestinal properties of COX-2 inhibitors; forfacilitating wound healing; for treating and/or preventing renal and/orrespiratory toxicity; and for treating and/or preventing COX-2 mediateddisorders (i.e., disorders resulting from elevated levels of COX-2) in apatient in need thereof which comprises administering to the patient atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally substituted with at least one NO₂ groupand/or at least one NO group (i.e., nitrosated and/or nitrosylatedrespectively), and, optionally, at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO•), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase and/orstimulates endogenous production of NO or EDRF in vivo and/or is asubstrate for nitric oxide synthase (i.e., NO donors). The methods canoptionally further comprise the administration of at least onetherapeutic agent, such as, for example, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. In this aspect of the invention, the methods can involveadministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosyalted, administering the COX-2 selectiveinhibitors, that are optionally nitrosated and/or nitrosylated and NOdonors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and therapeutic agents, oradministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosylated, NO donors and therapeutic agents. Theselective COX-2 inhibitors, nitric oxide donors, and/or therapeuticagents can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

Yet another aspect of the invention provides methods for improving thecardiovascular profile of COX-2 selective inhibitors in a patient inneed thereof which comprises administering to the patient atherapeutically effective amount of at least one COX-2 selectiveinhibitor, optionally substituted with at least one NO₂ and/or NO group(i.e. nitrosated and/or nitrosylated), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO•), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase and/or stimulates endogenous production of NO or EDRF in vivoand/or is a substrate for nitric oxide synthase (i.e. NO donor). Themethods can optionally further comprise the administration of at leastone of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, andmixtures of two or more thereof. In this aspect of the invention, themethods can involve administering the nitrosated and/or nitrosylatedCOX-2 selective inhibitors, administering the COX-2 selectiveinhibitors, that are optionally nitrosated and/or nitrosylated, and NOdonors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and at least one of3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplateletagents, thrombin inhibitors or thromboxane inhibitors, or administeringthe COX-2 selective inhibitors, that are optionally nitrosated and/ornitrosylated, NO donors, and at least one of 3-hydroxy-3methylglutarylcoenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombininhibitors or thromboxane inhibitors. The COX-2 inhibitors, nitric oxidedonors, and/or 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA)inhibitors, antiplatelet agents, thrombin inhibitors or thromboxaneinhibitors can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

In yet another aspect the invention provides kits comprising at leastone COX-2 selective inhibitor, that is optionally substituted at leastone NO₂ group and/or at least one NO group (i.e., nitrosated and/ornitrosylated respectively), and, optionally, at least one compound thatdonates, transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO•), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase. The kitcan further comprise at least one therapeutic agent, such as, forexample, steroids, nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. The COX-2 selective inhibitor, the nitric oxide donor and/ortherapeutic agent, can be separate components in the kit or can be inthe form of a composition in one or more pharmaceutically acceptablecarriers.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Cyclooxygenase-2 (COX-2) selective inhibitor” refers to a compound thatselectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. In one embodiment, the compound has acyclooxygenase-2 IC₅₀ of less than about 2 μM and a cyclooxygenase-1IC₅₀ of greater than about 5 μM, in the human whole blood COX-2 assay(as described in Brideau et al., Inflamm Res., 45: 68–74 (1996)) andalso has a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 10, and preferably of at least40. In another embodiment, the compound has a cyclooxygenase-1 IC₅₀ ofgreater than about 1 μM, and preferably of greater than 20 μM. Thecompound can also inhibit the enzyme, lipoxygenase. Such selectivity mayindicate an ability to reduce the incidence of common NSAID-induced sideeffects.

“Parent COX-2 inhibitor” refers to a non-nitrosated and/ornon-nitrosylated COX-2 inhibitor, or pharmaceutically acceptable saltsthereof or pharmaceutically acceptable esters thereof. “Parent COX-2inhibitor” includes the compounds of Formula (I) before they arenitrosated and/or nitrosylated by the methods described herein.

“Therapeutic agent” includes any therapeutic agent that can be used totreat or prevent the diseases described herein. “Therapeutic agents”include, for example, steroids, nonsteroidal anti-inflammatorycompounds, 5-lipoxygenase inhibitors, leukotriene B₄ receptorantagonists, leukotriene A₄ hydrolase inhibitors,3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. Therapeutic agentincludes the pro-drugs and pharmaceutical derivatives thereof includingbut not limited to the corresponding nitrosated and/or nitrosylatedderivatives. Although nitric oxide donors have therapeutic activity, theterm “therapeutic agent” does not include the nitric oxide donorsdescribed herein, since nitric oxide donors are separately defined.

“Cardiovascular disease or disorder” refers to any cardiovasculardisease or disorder known in the art, including, but not limited to,restenosis, atherosclerosis, atherogenesis, angina, (particularlychronic, stable angina pectoris), ischemic disease, congestive heartfailure or pulmonary edema associated with acute myocardial infarction,thrombosis, controlling blood pressure in hypertension (especiallyhypertension associated with cardiovascular surgical procedures),thromboemboembolic events, platelet aggregation, platelet adhesion,smooth muscle cell proliferation, vascular complications associated withthe use of medical devices, wounds associated with the use of medicaldevices, cerebrovascular ischemic events, and the like. Complicationsassociated with the use of medical devices may occur as a result ofincreased platelet deposition, activation, thrombus formation orconsumption of platelets and coagulation proteins. Such complications,which are within the definition of “cardiovascular disease or disorder,”include, for example, myocardial infarction, ischemic stroke, transientischemic stroke, thromboemboembolic events, pulmonary thromboembolism,cerebral thromboembolism, thrombophlebitis, thrombocytopenia, bleedingdisorders and/or any other complications which occur either directly orindirectly as a result of the foregoing disorders.

“Restenosis” is a cardiovascular disease or disorder that refers to theclosure of a peripheral or coronary artery following trauma to theartery caused by an injury such as, for example, angioplasty, balloondilation, atherectomy, laser ablation treatment or stent insertion.Restenosis can also occur following a number of invasive surgicaltechniques, such as, for example, transplant surgery, vein grafting,coronary artery bypass surgery, endarterectomy, heart transplantation,balloon angioplasty, atherectomy, laser ablation, endovascular stenting,and the like.

“Atherosclerosis” is a form of chronic vascular injury in which some ofthe normal vascular smooth muscle cells in the artery wall, whichordinarily control vascular tone regulating blood flow, change theirnature and develop “cancer-like” behavior. These vascular smooth musclecells become abnormally proliferative, secreting substances such asgrowth factors, tissue-degradation enzymes and other proteins, whichenable them to invade and spread into the inner vessel lining, blockingblood flow and making that vessel abnormally susceptible to beingcompletely blocked by local blood clotting, resulting in the death ofthe tissue served by that artery. Atherosclerotic cardiovasculardisease, coronary heart disease (also known as coronary artery diseaseor ischemic heart disease), cerebrovascular disease and peripheralvessel disease are all common manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

“Improving the cardiovascular profile” refers to and includes reducingthe risk of thromboembolic events, reducing the risk of developingatherosclerosis and atherosclerotic diseases, and inhibiting plateletaggregation of the parent COX-2 inhibitor.

“Thromboemboembolic events” includes, but is not limited to, ischemicstroke, transient ischemic stroke, myocardial infarction, anginapectoris, thrombosis, thromboembolism, thrombotic occlusion andreocclusion, acute vascular events, restenosis, transient ischemicattacks, and first and subsequent thrombotic stroke. Patients who are atrisk of developing thromboembolic events, may include those with afamilial history of, or genetically predisposed to, thromboembolicdisorders, who have had ischemic stroke, transient ischemic stroke,myocardial infarction, and those with unstable angina pectoris orchronic stable angina pectoris and patients with alteredprostacyclin/thromboxane A₂ homeostasis or higher than normalthromboxane A₂ levels leading to increase risk for thromboembolism,including patients with diabetes and rheumatoid arthritis.

“Thromboxane inhibitor” refers to any compound that reversibly orirreversibly inhibits thromboxane synthesis, and includes compoundswhich are the so-called thromboxane A₂ receptor antagonists, thromboxaneA₂ antagonists, thromboxane A₂/prostaglandin endoperoxide antagonists,thromboxane receptor (TP) antagonists, thromboxane antagonists,thromboxane synthase inhibitors, and dual acting thromboxane synthaseinhibitors and thromboxane receptor antagonists. The characteristics ofthe preferred thromboxane inhibitor should include the suppression ofthromboxane A₂ formation (thromboxane synthase inhibitors) and/orblockade of thromboxane A₂ and prostaglandin H₂ platelet and vessel wall(thromboxane receptor antagonists). The effects should block plateletactivation and therefore platelet function.

“Thromboxane A₂ receptor antagonist” refers to any compound thatreversibly or irreversibly blocks the activation of any thromboxane A₂receptor.

“Thromboxane synthase inhibitor” refers to any compound that reversiblyor irreversibly inhibits the enzyme thromboxane synthesis therebyreducing the formation of thromboxane A₂. Thromboxane synthaseinhibitors may also increase the synthesis of antiaggregatoryprostaglandins including prostacyclin and prostaglandin D₂. ThromboxaneA₂ receptor antagonists and thromboxane synthase inhibitors and can beidentified using the assays described in Tai, Methods of Enzymology,Vol. 86, 110–113 (1982); Hall, Medicinal Research Reviews, 11:503–579(1991) and Coleman et al., Pharmacol Rev., 46: 205–229 (1994) andreferences therein, the disclosures of which are incorporated herein byreference in its entirety.

“Dual acting thromboxane receptor antagonist and thromboxane synthaseinhibitor” refers to any compound that simultaneously acts as athromboxane A₂ receptor antagonist and a thromboxane synthase inhibitor.

“Thrombin inhibitors” refers to and includes compounds that inhibithydrolytic activity of thrombin, including the catalytic conversion offibrinogen to fibrin, activation of Factor V to Va, Factor VIII toVIIIa, Factor XIII to XIIIa and platelet activation. Thrombin inhibitorsmay be identified using assays described in Lewis et at., ThrombosisResearch. 70: 173–190 (1993).

“Platelet aggregation” refers to the binding of one or more platelets toeach other. Platelet aggregation is commonly referred to in the contextof generalized atherosclerosis, not with respect to platelet adhesion onvasculature damaged as a result of physical injury during a medicalprocedure. Platelet aggregation requires platelet activation whichdepends on the interaction between the ligand and its specific plateletsurface receptor.

“Platelet activation” refers either to the change in conformation(shape) of a cell, expression of cell surface proteins (e.g., theIIb/IIIa receptor complex, loss of GPIb surface protein), and secretionof platelet derived factors (e.g., serotonin, growth factors).

“Patient” refers to animals, preferably mammals, most preferably humans,and includes males and females, and children and adults.

“Therapeutically effective amount” refers to the amount of the compoundand/or composition that is effective to achieve its intended purpose.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Nitric oxide adduct” or “NO adduct” refers to compounds and functionalgroups which, under physiological conditions, can donate, release and/ordirectly or indirectly transfer any of the three redox forms of nitrogenmonoxide (NO⁺, NO⁻, NO∘), such that the biological activity of thenitrogen monoxide species is expressed at the intended site of action.

“Nitric oxide releasing” or “nitric oxide donating” refers to methods ofdonating, releasing and/or directly or indirectly transferring any ofthe three redox forms of nitrogen monoxide (NO⁺, NO⁻, NO∘), such thatthe biological activity of the nitrogen monoxide species is expressed atthe intended site of action.

“Nitric oxide donor” or “NO donor” refers to compounds that donate,release and/or directly or indirectly transfer a nitrogen monoxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

“Alkyl” refers to a lower alkyl group, a haloalkyl group, a hydroxyalkylgroup, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, acycloalkyl group or a heterocyclic ring, as defined herein. An alkylgroup may also comprise one or more radical species, such as, forexample a cycloalkylalkyl group or a heterocyclicalkyl group.

“Lower alkyl” refers to branched or straight chain acyclic alkyl groupcomprising one to about ten carbon atoms (preferably one to about eightcarbon atoms, more preferably one to about six carbon atoms). Exemplarylower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl,and the like.

“Substituted lower alkyl” refers to a lower alkyl group, as definedherein, wherein one or more of the hydrogen atoms have been replacedwith one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently ahydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an aminogroup, as defined herein.

“Haloalkyl” refers to a lower alkyl group, an alkenyl group, an alkynylgroup, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclicring, as defined herein, to which is appended one or more halogens, asdefined herein. Exemplary haloalkyl groups include trifluoromethyl,chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to a branched or straight chain C₂–C₁₀ hydrocarbon(preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆ hydrocarbon)that can comprise one or more carbon-carbon double bonds. Exemplaryalkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl,2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl,octen-1-yl, and the like.

“Lower alkenyl” refers to a branched or straight chain C₂–C₄ hydrocarbonthat can comprise one or two carbon-carbon double bonds.

“Substituted alkenyl” refers to a branched or straight chain C₂–C₁₀hydrocarbon (preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds,wherein one or more of the hydrogen atoms have been replaced with one ormore R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy, an oxo,a carboxyl, a carboxamido, a halo, a cyano or an amino group, as definedherein.

“Alkynyl” refers to an unsaturated acyclic C₂–C₁₀ hydrocarbon(preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆ hydrocarbon)that can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethylbutyn-1-yl, and the like.

“Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2. 1)heptyl,8-azabicyclo(3,2, 1)oct-2-enyl and the like.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarboncomprising from about 3 to about 10 carbon atoms. Cycloalkyl groups canbe unsubstituted or substituted with one, two or three substituentsindependently selected from alkyl, alkoxy, amino, alkylamino,dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl,ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike.

“Heterocyclic ring or group” refers to a saturated or unsaturated cyclichydrocarbon group having about 2 to about 10 carbon atoms (preferablyabout 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms arereplaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfurmaybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl,furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl,1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, andthe like.

“Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

“Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclicring system comprising one or two aromatic rings. Exemplary aryl groupsinclude phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl,indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclicaryl groups) can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, alkylthio,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester,alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid,arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester,carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary substituted aryl groups includetetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl,arylsulfonyl, and the like.

“Cycloalkenyl” refers to an unsaturated cyclic C₂–C₁₀ hydrocarbon(preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds.

“Alkylaryl” refers to an alkyl group, as defined herein, to which isappended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

“Arylalkyl” refers to an aryl radical, as defined herein, attached to analkyl radical, as defined herein. Exemplary arylalkyl groups includebenzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl, and the like.

“Arylalkenyl” refers to an aryl radical, as defined herein, attached toan alkenyl radical, as defined herein. Exemplary arylalkenyl groupsinclude styryl, propenylphenyl, and the like.

“Cycloalkylalkyl” refers to a cycloalkyl radical, as defined herein,attached to an alkyl radical, as defined herein.

“Cycloalkylalkoxy” refers to a cycloalkyl radical, as defined herein,attached to an alkoxy radical, as defined herein.

“Cycloalkylalkylthio” refers to a cycloalkyl radical, as defined herein,attached to an alkylthio radical, as defined herein.

“Heterocyclicalkyl” refers to a heterocyclic ring radical, as definedherein, attached to an alkyl radical, as defined herein.

“Arylheterocyclic ring” refers to a bi- or tricyclic ring comprised ofan aryl ring, as defined herein, appended via two adjacent carbon atomsof the aryl ring to a heterocyclic ring, as defined herein. Exemplaryarylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

“Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group or a haloalkyl group, as definedherein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy,cyclopentyloxy, trifluoromethoxy, and the like.

“Aryloxy” refers to R₅₅O—, wherein R₅₅ is an aryl group, as definedherein. Exemplary arylkoxy groups include napthyloxy, quinolyloxy,isoquinolizinyloxy, and the like.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein.

“Lower alkylthio” refers to a lower alkyl group, as defined herein,appended to a thio group, as defined herein.

“Arylalkoxy” or “alkoxyaryl” refers to an alkoxy group, as definedherein, to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

“Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended toan alkyl group, as defined herein. Exemplary alkoxyalkyl groups includemethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

“Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appendedto a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkylgroups include 4-methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

“Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkylthiogroups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and thelike.

“Haloalkoxy” refers to an alkoxy group, as defined herein, in which oneor more of the hydrogen atoms on the alkoxy group are substituted withhalogens, as defined herein. Exemplary haloalkoxy groups include1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

“Hydroxy” refers to —OH.

“Oxo” refers to ═O.

“Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganic cation.

“Oxime” refers to (═N—OR₈₁) wherein R₈₁ is a hydrogen, an alkyl group,an aryl group, an alkylsulfonyl group, an arylsulfonyl group, acarboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, acarboxamido group, an alkoxyalkyl group or an alkoxyaryl group.

“Hydrazone refers to (═N—N(R₈₁)(R′₈₁)) wherein R′₈₁ is independentlyselected from R₈₁, and R₈₁ is as defined herein.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted ammonium cations, and thelike.

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations such as for example,sodium, potassium, and the like.

“Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended toan alkyl group, as defined herein.

“Nitrate” refers to —O—NO₂.

“Nitrite” refers to —O—NO.

“Thionitrate” refers to —S—NO₂.

“Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO₂ and “nitrosated” refers to compoundsthat have been substituted therewith.

“Nitroso” refers to the group —NO and “nitrosylated” refers to compoundsthat have been substituted therewith.

“Nitrile” and “cyano” refer to —CN.

“Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (Cl),and/or fluorine (F).

“Amino” refers to —NH₂, an alkylamino group, a dialkylamino group, anarylamino group, a diarylamino group, an alkylarylamino group or aheterocyclic ring, as defined herein.

“Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkylamino groups include methylamino, ethylamino,butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, as definedherein.

“Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

“Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

“Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, wherein R₅₂ is analkyl group, as defined herein, and R₅₅ is an aryl group, as definedherein.

“Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkyl group,as defined herein, and R₇₉ is an arylalkyl group, as defined herein.

“Alkylcycloalkylamino” refers to R₅₂R₈₀N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₈₀ is an cycloalkyl group, as definedherein.

“Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

“Aminoaryl” refers to an aryl group to which is appended an alkylaminogroup, a arylamino group or an arylalkylamino group. Exemplary aminoarylgroups include anilino, N-methylanilino, N-benzylanilino, and the like.

“Thio” refers to —S—.

“Sulfinyl” refers to —S(O)—.

“Methanthial” refers to —C(S)—.

“Thial” refers to ═S.

“Sulfonyl” refers to —S(O)₂ ⁻.

“Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

“Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an aryl group, as defined herein

“Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkyl group, anaryl group, or an aryl heterocyclic ring, as defined herein.

“Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an aryl group, as defined herein.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group, as defined herein).

“Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, as definedherein.

“Arylalkylthio” refers to an aryl group, as defined herein, appended toan alkylthio group, as defined herein.

“Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is an alkylgroup, as defined herein.

“Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an aryl group,as defined herein.

“Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

“Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, an alkylgroup, an aryl group or an arylheterocyclic ring, as defined herein.

“Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, an organiccation or an inorganic cation, as defined herein.

“Carbonyl” refers to —C(O)—.

“Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkyl group, asdefined herein.

“Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylalkylcarbonyl” refers to R₅₅–R₅₂—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Alkylarylcarbonyl” refers to R₅₂–R₅₅—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

“Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkyl group,an aryl group or an aryl heterocyclic ring, as defined herein.

“Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, asdefined herein, appended to a carboxyl group, as defined herein.

“Alkylcarboxylic ester” refers to an alkyl group, as defined herein,appended to a carboxylic ester group, as defined herein.

“Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

“Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, asdefined herein, appended to a carboxylic ester group, as defined herein.

“Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylcarboxamido” refers to an alkyl group, as defined herein, appendedto a carboxarnido group, as defined herein.

“Arylcarboxamido” refers to an aryl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, and R₅₉ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lone pair ofelectrons, thial or oxo, and R₇₁ and R₇₂ are each independently acovalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

Compounds that donate, transfer or release nitric oxide species in vivohave been recognized as having a wide spectrum of advantages andapplications. The invention is based on the unexpected discovery of theeffects of such compounds alone and together with one or more COX-2inhibitors. Treatment or prevention of inflammation, pain and fever;treatment and/or improvement of the gastrointestinal properties of COX-2inhibitors; facilitation of wound healing; and treatment and/orprevention of renal and/or respiratory toxicity and cyclooxygenase-2mediated disorders can be obtained by the use of COX-2 inhibitors of theinvention; or by the use of COX-2 inhibitors in conjunction with one ormore compounds that donate, release or transfer nitric oxide and/orstimulate endogenous production of NO and/or EDRF in vivo and/or is asubstrate for nitric oxide synthase, and, optionally, with one or moretherapeutic agents.

The COX-2 selective inhibitors, that are optionally nitrosated and/ornitrosylated, can be used alone or in conjunction with one or morecompounds that donate, release or transfer nitric oxide and/or stimulateendogenous production of NO and/or EDRF in vivo and/or is a substratefor nitric oxide synthase, and/or with one or more therapeutic agents,such as for example, steroids, nonsterodal anti-inflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and mixturesof two or more thereof. These novel compounds and novel compositions ofthe present invention are described in more detail herein.

In one embodiment, the invention described compounds of Formula (I), andpharmaceutically acceptable salts thereof;

wherein:

R₄ is methyl or ethyl;

R₅ is chloro or fluoro;

R₆ is hydrogen or fluoro;

R₇ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy orhydroxyl;

R₈ is hydrogen or fluoro;

R₉ is chloro, fluoro, triflurormethyl or methyl;

X is an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—;

K is:

a)—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—T—Q;or

b)—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—R₃and with the proviso that at least one R_(e) is selected as —T—Q, or—(C(R_(g))(R_(h)))_(k)—T—Q when K is (b); and with the further provisothat “X—K” in the compounds of Formula (I), does not include nitroxyllower alkyl esters such as 4-(nitroxyl)butyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate as disclosedin WO 99/11605;

R₃ is:

Q is —NO or —NO₂;

a, b, c, d, g, i and j are each independently an integer from 0 to 3;

p, x, y and z are each independently an integer from 0 to 10;

W at each occurrence is independently —C(O)—, —C(S)—, —T—,—(C(R_(e))(R_(f)))_(h)—, an alkyl group, an aryl group, a heterocyclicring, an arylheterocyclic ring, or —(CH₂CH₂O)_(q)—;

E at each occurrence is independently —T—, an alkyl group, an arylgroup, —(C(R_(e))(R_(f)))_(h)—, a heterocyclic ring, an arylheterocyclicring, or —(CH₂CH₂O)_(q)—;

h is an integer form 1 to 10;

q is an integer from 1 to 5;

R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, analkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, acycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester,an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, analkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, anarylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, analkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, asulfonic ester, a urea, a phosphoryl, a nitro, W_(h), —T—Q, or—(C(R_(g))(R_(h)))_(k)—T—Q, or R_(e) and R_(f) taken together with thecarbons to which they are attached form a carbonyl, a methanthial, aheterocyclic ring, a cycloalkyl group, an aryl group, an oxime, ahydrazone or a bridged cycloalkyl group;

R_(g) and R_(h) at each occurrence are independently R_(e);

k is an integer from 1 to 3;

T at each occurrence is independently a covalent bond, a carbonyl, anoxygen, —S(O)_(o)— or —N(R_(a))R_(i)—;

o is an integer from 0 to 2;

R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;

R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester,an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl,an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl,arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, anaminoalkyl, an aminoaryl, —CH₂—C(T—Q)(R_(e))(R_(f)), a bond to anadjacent atom creating a double bond to that atom, —(N₂O₂—)⁻∘M⁺, whereinM⁺ is an organic or inorganic cation;

with the proviso that the nitrosated and/or nitrosylated compounds ofFormula (I) must contain at least one —NO group or at least one —NO₂group, and wherein the at least one —NO group or the at least one —NO₂group is linked to the compounds of Formula (I) through an oxygen atom,a nitrogen atom or a sulfur atom.

In cases where R_(e) and R_(f) are a heterocyclic ring or R_(e) andR_(f) taken together with the carbon atoms to which they are attachedare a heterocyclic ring, then R_(i) can be a substituent on anydisubstituted nitrogen contained within the radical where R_(i) is asdefined herein.

In cases where multiple designations of variables that are in sequenceare selected as a “covalent bond” or the integer selected is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E—E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

In a preferred embodiment of the invention, the parent COX-2 selectiveinhibitor is 2(2-((2-chloro-6-fluorophenyl)amino)₅-methylphenyl) aceticacid (COX 189, registration number 220991-20-8), and its derivatives, asdisclosed in, for example, WO 99/11605, WO 01/23346 and WO 02/20090, thedisclosures of each of which are incorporated by reference herein intheir entirety. The structure of the preferred embodiment parent COX-2selective inhibitor,2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid (COX189), is shown below:

In other preferred embodiments of the invention, the nitrosatedderivatives of the compounds of Formula (I) are the nitrosatedderivatives of the COX-2 selective inhibitor,2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid (COX189). In even more preferred embodiments of the invention the nitrosatedderivatives of the COX-2 selective inhibitor, COX-189, are compounds ofFormula (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) andpharmaceutically acceptable salts thereof:

wherein the compound of Formula (II), 2-(2-(nitroxy)ethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (III), 2-(2-(nitroxy)ethoxy)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (IV), 3-((nitroxy)methylphenyl)2(2-((2-chloro-6-fluorophenyl) amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (V), 2,3-bis(nitroxy)propyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (VI),6-(nitroxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl2-(2((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (VII), 2-((2-(nitroxy)ethyl)sulfonyl)ethyl 2(2-((2chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (VIII),2-(4-(2-nitrooxyl)ethyl)piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (IX),2,3-bis(nitroxy)-4-(2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetyloxy)butyl2-(2-((2-chloro-6-fluorophenyl)amino)5methylphenyl)acetate, is:

Another aspect of the invention describes the metabolites of thecompounds of Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX)and pharmaceutically acceptable salts thereof. These metabolites,include but are not limited to, the non-nitrosated derivatives of thecompounds of Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX)and pharmaceutically acceptable salts thereof, such as, for example thecompounds of Formulas (X), (XI), (XII), (XIII), (XIV), (XV), (XVI) and(XVII):

wherein the compound of Formula (X), 2-(2-(hydroxyethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XI), 2-(2-(hydroxyethoxy)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XII), 3-(hydroxymethylphenyl)2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XIII), 2,3-dihydroxypropyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XIV),6-hydroxy-4,8-dioxabicyclo(3.3.0)oct-2-yl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XV), 2-((2-hydroxyethyl)sulfonyl) ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XVI),2-(4-(2-hydroxyethyl)piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

wherein the compound of Formula (XVII),4-(2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetoxy)-2,3-dihydroxybutyl-2-(2-((2-chloro-6-fluorophenyl)amino)5methylphenyl)acetyloxy)butylacetate, is:

Compounds of the invention that have one or more asymmetric carbon atomsmay exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. The invention includes within its scope all such isomers andmixtures thereof.

Another aspect of the invention provides processes for making the novelcompounds of the invention and to the intermediates useful in suchprocesses. The reactions are performed in solvents appropriate to thereagents and materials used are suitable for the transformations beingeffected. It is understood by one skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

The chemical reactions described herein are generally disclosed in termsof their broadest application for the preparation of the compounds ofthis invention. The chemical reactions are described by, for example,Smith and March, March's Advanced Organic Chemistry, Reactions,Mechanisms and Structure, Fifth Edition, John Wiley & Sons, New York(2001) and by Larock, Comprehensive Organic Transformations, VCHPublishers, Inc. (1989). The compounds of the invention can besynthesized in a number of ways well known to one skilled in the art oforganic synthesis. The compounds can be synthesized using the methodsdescribed herein, together with synthetic methods known in the art ofsynthetic organic chemistry, or by convention modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials. Methods for the preparation ofthe compounds, include, but are not limited to, those described below.All references cited herein are hereby incorporated herein by referencein their entirety.

Nitroso compounds of Formula (I), wherein R₄, R₅, R₆, R₇, R₈, and R₉ areas defined herein, and an O-nitrosylated ester is representative of the“X—K” group as defined herein may be prepared as described below. Anappropriate acid of the compound of Formula (I) (i.e., wherein “X—K” isan hydroxyl group) is converted into the ester by reaction with anappropriate monoprotected diol. Preferred methods for the preparation ofesters are coupling the acid and the monoprotected diol by treatmentwith a dehydration agent such as dicyclohexylcarbodiimide (DCC).Alternatively, the acid may first be converted into an alkali metal saltsuch as the sodium, potassium or lithium salt, and reacted with an alkylhalide that also contains a protected hydroxyl group in a polar solventsuch as DMF to produce the ester. Preferred protecting groups for thealcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichlormethane, THF, DMF or acetonitrile produces the compound ofFormula (I).

Nitroso compounds of Formula (I), wherein R₄, R₅, R₆, R₇, R₈, and R₉ areas defined herein, and a S-nitrosylated ester is representative of the“X—K” group as defined herein may be prepared as described below. Anappropriate acid of the compound of Formula (I) (i.e., wherein “X—K” isa hydroxyl group) is converted into the ester by reaction with anappropriate protected thiol containing alcohol. Preferred methods forthe preparation of esters are coupling the appropriate acid andprotected thiol-containing alcohol to produce the ester by treatmentwith a dehydration agent such as DCC. Alternatively, the acid may firstbe converted into an alkali metal salt such as the sodium, potassium orlithium salt, which is then reacted with an alkyl halide which alsocontains a protected thiol group in a polar solvent such as DMF toproduce the ester. Preferred protecting groups for the thiol moiety areas a thioester such as thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically used to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF or acetonitrile produces the compound of Formula (I).Alternatively, a stoichiometric quantity of sodium nitrite in an aqueousacid mixture produces the compound.of Formula (I).

The synthesis of the parent COX-2 inhibitors (i.e. non-nitrosated and/ornon-nitrosylated COX-2 inhibitors) are disclosed in, for example, WO99/11605, WO 01/23346 and WO 02/20090, the disclosures of each of whichare incorporated by reference herein in their entirety. The parent COX-2selective inhibitor can be nitrosated and/or nitrosylated through one ormore sites such as oxygen, sulfur and/or nitrogen using the methodsdescribed in the examples herein and using conventional methods known toone skilled in the art. For example, known methods for nitrosating andnitrosylating compounds are described in U.S. Pat. Nos. 5,380,758 and5,703,073; 6,297,260, WO 97/27749; WO 98/19672; WO 01/45703; and Oae etal, Org. Prep. Proc. Int., 15(3): 165–198 (1983), the disclosures ofeach of which are incorporated by reference herein in their entirety.The methods of nitrosating and/or nitrosylating the compounds in thesereferences can be applied by one skilled in the art to produce any ofthe nitrosated and/or nitrosylated compounds of Formula (I) describedherein. The nitrosated and/or nitrosylated compounds of Formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) (i.e. nitrosatedand/or nitrosylated COX-2 selective inhibitors) of the invention donate,transfer or release a biologically active form of nitrogen monoxide(nitric oxide).

The nitrosated compounds of Formula (II), (III), (IV), (V), (VI), (VII),(VIII) or (IX) can be synthesized using the methods for nitrosatingnon-steroidal antinflammatory compounds (NSAIDs) disclosed in, forexample, WO 94/03421, WO 94/04484, WO 94/12463, WO 95/09831, WO95/30641, WO 01/00563 and WO 01/04082, WO 01/10814 and in U.S.Application No. 60/418,353; the disclosures of each of which areincorporated by reference herein in their entirety.

The compounds of the invention include the parent COX-2 inhibitors,including those described herein, which have been nitrosated and/ornitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Thenitrosated and/or nitrosylated COX-2 inhibitors of the invention donate,transfer or release a biologically active form of nitrogen monoxide(i.e., nitric oxide).

Nitrogen monoxide can exist in three forms: NO− (nitroxyl), NO•(uncharged nitric oxide) and NO⁺(nitrosonium). NO• is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO•),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO− arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

Compounds contemplated for use in the invention (e.g., COX-2 selectiveinhibitor, that can be optionally nitrosated and/or nitrosylated, are,optionally, used in combination with nitric oxide and compounds thatrelease nitric oxide or otherwise directly or indirectly deliver ortransfer a biologically active form of nitrogen monoxide to a site ofits intended activity, such as on a cell membrane in vivo.

The term “nitric oxide” encompasses uncharged nitric oxide (NO•) andcharged nitrogen monoxide species, preferably charged nitrogen monoxidespecies, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO−). Thereactive form of nitric oxide can be provided by gaseous nitric oxide.The nitrogen monoxide releasing, delivering or transferring compoundshave the structure F—NO, wherein F is a nitrogen monoxide releasing,delivering or transferring moiety, and include any and all suchcompounds which provide nitrogen monoxide to its intended site of actionin a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamide (FK-409),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamines, N-((2Z,3E)-4-ethyl-2-(hydroxyamino)-6-methyl-5-nitro-3-heptenyl)-3-pyridinecarboxamide(FR 146801), nitrosoamines, furoxans as well as substrates for theendogenous enzymes which synthesize nitric oxide. NONOates include, butare not limited to,(Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino))diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate(“PAPA/NO”),(Z)-1-(N-(3-aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino)diazen-1-ium-1,2-diolate (spermine NONOate or “SPER/NO”) andsodium(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamineNONOate or “DEA/NO”) and derivatives thereof. NONOates are alsodescribed in U.S. Pat. Nos. 6,232,336, 5,910,316 and 5,650,447, thedisclosures of which are incorporated herein by reference in theirentirety. The “NO adducts” can be mono-nitrosylated, poly-nitrosylated,mono-nitrosated and/or poly-nitrosated at a variety of naturallysusceptible or artificially-provided binding sites for biologicallyactive forms of nitrogen monoxide.

One group of NO adducts is the S-nitrosothiols, which are compounds thatinclude at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5–200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165–198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

Another embodiment of the invention is S-nitroso amino acids where thenitroso group is linked to a sulfur group of a sulfur-containing aminoacid or derivative thereof. Such compounds include, for example,S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins; heme proteins,such as hemoglobin and serum albumin; and biologically protectiveproteins, such as immunoglobulins, antibodies and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

Other examples of suitable S-nitrosothiols include:

(i) HS(C(R_(e))(R_(f)))_(m)SNO;

(ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); or

(iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

wherein m is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, -T-Q, or —(C(R_(g))(R_(h)))_(k)-T-Qor R_(e) and R_(f) taken together are an oxo, a methanthial, aheterocyclic ring, a cycloalkyl group, an oxime, a hydrazone or abridged cycloalkyl group; Q is —NO or —NO₂; and T is independently acovalent bond, a carbonyl, an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—,wherein o is an integer from 0 to 2, R_(a) is a lone pair of electrons,a hydrogen or an alkyl group; R_(i) is a hydrogen, an alkyl, an aryl, analkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester,an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, analkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl,an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, acarboxylic ester, an aminoalkyl, an aminoaryl,—CH2—C(T-Q)(R_(g))(R_(h)), or —(N₂O₂−)⁻•M⁺, wherein M⁺is an organic orinorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(g))(R_(h)) or —(N₂O₂—)•M⁺; then “-T-Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group; and

R_(g) and R_(h) at each occurrence are independently R_(e);

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical wherein R_(i)is as defined herein.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

Another group of NO adducts for use in the invention, where the NOadduct is a compound that donates, transfers or releases nitric oxide,include compounds comprising at least one ON—O— or ON—N— group. Thecompounds that include at least one ON—O— or ON—N— group are preferablyON—O— or ON—N-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); ON—O— or ON—N-amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixtures);ON—O— or ON—N-sugars; ON—O— or —ON—N— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5–200nucleotides); ON—O— or ON—N— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

Another group of NO adducts for use in the invention include nitratesthat donate, transfer or release nitric oxide, such as compoundscomprising at least one O₂N—O—, O₂N—N— or O₂N—S— group. Preferred amongthese compounds are O₂N—O—, O₂N—N—or O₂N—S-polypeptides (the term“polypeptide” includes proteins and also polyamino acids that do notpossess an ascertained biological function, and derivatives thereof);O₂N—O—, O₂N—N— or O₂N—S-amino acids (including natural and syntheticamino acids and their stereoisomers and racemic mixtures); O₂N—O—,O₂N—N— or O₂N—S— sugars; O₂N—O—, O₂N—N— or O₂N—S— modified andunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5–200 nucleotides); O₂N—O—, O₂N—N— or O₂N—S— straight orbranched, saturated or unsaturated, aliphatic or aromatic, substitutedor unsubstituted hydrocarbons; and O₂N—O—, O₂N—N— or O₂N—S— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group include isosorbide dinitrate, isosorbidemononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate,nitroglycerin, pentaerythritoltetranitrate, pentrinitrol,propatylnitrate and organic nitrates with a sulfhydryl-containing aminoacid such as, for example SPM 3672, SPM 5185, SPM 5186 and thosedisclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847and 5,883,122 and in WO 97/46521, WO 00/54756 and in WO 03/013432, thedisclosures of each of which are incorporated by reference herein intheir entirety.

Another group of NO adducts are N-oxo-N-nitrosoamines that donate,transfer or release nitric oxide and are represented by the formula:R^(1″)R^(2″)N—N(O—M⁺)—NO, where R^(1″) and R^(2″) are each independentlya polypeptide, an amino acid, a sugar, a modified or unmodifiedoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and where M⁺ is an organic or inorganic cation, suchas, for example, an alkyl substituted ammonium cation or a Group I metalcation.

The invention is also directed to compounds that stimulate endogenous NOor elevate levels of endogenous endothelium-derived relaxing factor(EDRF) in vivo or are substrates for nitric oxide synthase. Suchcompounds include, for example, L-arginine, L-homoarginine, andN-hydroxy-L-arginine, including their nitrosated and nitrosylatedanalogs (e.g., nitrosated L-arginine, nitrosylated L-arginine,nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,nitrosated L-homoarginine and nitrosylated L-homoarginine), precursorsof L-arginine and/or physiologically acceptable salts thereof,including, for example, citrulline, omithine, glutamine, lysine,polypeptides comprising at least one of these amino acids, inhibitors ofthe enzyme arginase (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and/orphysiologically acceptable salts thereof, including, for example,pyruvate, pyruvate precursors, α-keto acids having four or more carbonatoms, precursors of α-keto acids having four or more carbon atoms (asdisclosed in WO 03/017996, the disclosure of which is incorporatedherein in its entirety), and the substrates for nitric oxide synthase,cytokines, adenosin, bradykinin, calreticulin, bisacodyl, andphenolphthalein. EDRF is a vascular relaxing factor secreted by theendothelium, and has been identified as nitric oxide (NO) or a closelyrelated derivative thereof (Palmer et al, Nature, 327:524–526 (1987);Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265–9269 (1987)).

The invention is also based on the discovery that compounds andcompositions of the invention may be used in conjunction with othertherapeutic agents for co-therapies, partially or completely, in placeof other conventional anti-inflammatory compounds, such as, for example,together with steroids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H₂ receptorantagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opiods, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof.

Leukotriene A₄ (LTA₄) hydrolase inhibitors refer to compounds thatselectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of less thanabout 10 μM, and preferably with an IC₅₀ of less than about 1 μM.Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino4-(4-benzyloxyphenyl)-2-hydroxybutyric acidbenzyl ester,N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine,7-(4-(4-ureidobenzyl)phenyl) heptanoic acid and 3(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, andmixtures of two or more thereof.

Suitable LTB₄ receptor antagonists include, but are not limited to,ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270;CGS-25019C; ETH-615; MAFP; TMK-688; T-0757; LY 213024, LY 210073, LY223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111;ONO-LB457, ONO-4057, and ONO-LB448, S-2474, calcitrol; PF 10042; Pfizer105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228;SB-201146 and SB-209247; SKF-104493; SM 15178; TMK-688; BPC 15, andmixtures of two or more thereof. The preferred LTB₄ receptor antagonistsare calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-2931 11,ONO-4057 and TMK-688, and mixtures of two or more thereof.

Suitable 5-LO inhibitors include, but are not limited to, A-76745, 78773and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322; ML-3000;PF-5901; R-840; rilopirox, flobufen, linasolast, lonapolene, masoprocol,ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox,flezelastine hydrochloride, enazadrem phosphate, and bunaprolast, andmixtures of two or more thereof. Suitable 5-LO inhibitors are alsodescribed more fully in WO 97/29776, the disclosure of which isincorporated herein by reference in its entirety.

Suitable 5-HT agonists, include, but are not limited to, rizatriptan,sumatriptan, naratriptan, zolmitroptan, eleptriptan, almotriptan, ergotalkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable5-HT agonists are described more fully in WO 0025779, and in WO00/48583. 5-HT agonists refers to a compound that is an agonist to any5-HT receptor, including but not limited to, 5-HT₁ agonists, 5-HT_(1B)agonists and 5-HT_(1D) agonists, and the like.

Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, 13^(th) Edition.

Suitable HMG CoA inhibitors, include, but are not limited to, reductaseand synthase inhibitors, such as, for example, squalene synthetaseinhibitors, benzodiazepine squalene synthase inhibitors, squaleneepoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like. Suitable HMG CoAinhibitors include simvastatin, pravastatin, lovastatin, mevastatin,fluvastatin, atorvastatin, cerivastatin, and the like, and are describedmore fully in U.S. Pat. No. 6,245,797 and WO 99/20110, the disclosuresof which are incorporated herein by reference in their entirety.

Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen, indomethacin, andthe like. Suitable NSAIDs are described more fully in the literature,such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics(9th Edition), McGraw-Hill, 1995, Pgs. 617–657; the Merck Index onCD-ROM, 13^(th) Edition; and in U.S. Pat. Nos. 6,057,347 and 6,297,260assigned to NitroMed Inc., the disclosures of which are incorporatedherein by reference in their entirety.

Suitable H₂ receptor anatgonists, include, but are not limited to,cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901–915; the Merck Index on CD-ROM,13^(th) Edition; and in WO 00/28988 assigned to NitroMed Inc., thedisclosures of which are incorporated herein by reference in theirentirety.

Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described in U.S. Pat. No. 6,025,353 and WO 00/38730, thedisclosures of which are incorporated herein by reference in theirentirety.

Suitable antiplatelet agents, include but are not limited to, aspirin,ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIa receptorantagonists, and the like. Suitable antineoplastic agents are alsodescribed in WO 99/45913, the disclosure of which is incorporated hereinby reference in its entirety. In a preferred embodiment of theinvention, the antiplatelet agent is aspirin, more preferably, low-doseaspirin (i.e. 75 mg–100 mg/day).

Suitable thrombin inhibitors, include but are not limited to,N′-((1-(aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-prolineamide),3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone,3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone,and the like. Suitable thrombin inhibitors are also described in WO00/18352, the disclosure of which is incorporated herein by reference inits entirety.

Suitable thromboxane inhibitors, include but are not limited tothromboxane synthase inhibitors, thromboxane receptor antagonists, andthe like. Suitable thromboxane inhibitors, are also described in WO01/87343, the disclosure of which is incorporated herein by reference inits entirety.

Suitable decongestants include, but are not limited to, phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine, andthe like.

Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

Suitable proton pump inhibitors, include, but are not limited to,omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, andthe like. Suitable proton pump inhibitors are described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901–915; theMerck Index on CD-ROM, 13^(th) Edition; and in WO 00/50037 assigned toNitroMed Inc., the disclosures of which are incorporated herein byreference in their entirety.

The compounds and compositions of the invention, may also be used incombination therapies with opioids and other analgesics, including, butnot limited to, narcotic analgesics, Mu receptor antagonists, Kappareceptor antagonists, non-narcotic (i.e. non-addictive) analgesics,monoamine uptake inhibitors, adenosine regulating agents, cannabinoidderivatives, neurokioin 1 receptor antagonists, Substance P antagonists,neurokinin-1 receptor antagonists, sodium channel blockers,N-methytl-D-aspartate receptor antagonists, and mixtures of two or morethereof. Preferred combination therapies would be with morphine,meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine,meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608,E-2078, ICI-204448, acctominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((−) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixturesof two or more thereof.

The compounds and compositions of the invention can also be used incombination with inducible nitric oxide synthase (iNOS) inhibitors.Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of eachof which are incorporated by reference herein in their entirety.

The invention is also based on the discovery that the administration ofa therapeutically effective amount of the compounds and compositionsdescribed herein is effective for treating inflammation, pain (bothchronic and acute), and fever, such as, for example, analgesic in thetreatment of pain, including, but not limited to headache, migraines,postoperative pain, dental pain, muscular pain, and pain resulting fromcancer; as an antipyretic for the treatment of fever, including but notlimited to, rheumatic fever, symptoms associated with influenza or otherviral infections, common cold, low back and neck pain, dysmenorrhea,headache, toothache, sprains, strains, myositis, neuralgia, synovitis;arthritis, including but not limited to rheumatoid arthritis,degenerative joint disease (osteoarthritis), spondyloarthropathies,gouty arthritis, systemic lupus erythematosus and juvenile arthritis.For example, the patient can be administered a therapeutically effectiveamount of least one nitrosated and/or nitrosylated derivative of theCOX-2 selective inhibitor of the invention. In another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one compound that donates, transfers orreleases nitric oxide, or elevates levels of endogenous EDRF or nitricoxide, or is a substrate for nitric oxide synthase. In yet anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated, and, at least one therapeutic agent,including byt not limited to, steroids, nonsterodal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, H₂ antagonists, antineoplastic agents, antiplatelet agents,thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics,sedating or non-sedating anti-histamines, inducible nitric oxidesynthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and,optionally, at least one compound that donates, transfers or releasesnitric oxide, or elevates levels of endogenous EDRF or nitric oxide, oris a substrate for nitric oxide synthase. The compounds can beadministered separately or in the form of a composition.

Another embodiment of the invention provides methods for decreasingand/or preventing gastrointestinal disorders and improving thegastrointestinal properties of the COX-2 selective inhibitor byadministering to the patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein, Suchgastrointestinal disorders refer to any disease or disorder of the uppergastrointestinal tract (e.g., esophagus, the stomach, the duodenum,jejunum) including, for example, inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome, ulcerative colitis, pepticulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux diseas, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated derivative of theCOX-2 selective inhibitor of the invention. In another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and at least one compound that donates, transfersor releases nitric oxide, or elevates levels of endogenous EDRF ornitric oxide, or is a substrate for nitric oxide synthase. In yetanother embodiment, the patient can be administered a therapeuticallyeffective amount of at least one COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, and, at least one therapeuticagent, including but not limited to, including but not limited to,steroids, nonsterodal anti-inflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

Yet another embodiment of the invention provides methods forfacilitating wound healing (such as, for example, ulcer healing, bonehealing including osteoporosis) by administering to the patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Wound refers to, and includes, any lesionthat is characterized by loss of tissue, and, includes, but are notlimited to, ulcers, cuts, burns, bone fractures, orthopedic procedure,would infliction, and the like. Ulcers refers to lesions of the uppergastrointestinal tract lining that are characterized by loss of tissue,and, include, but are not limited to, gastric ulcers, duodenal ulcers,gastritis, and the like. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated derivative of the COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide, orelevates levels of endogenous EDRF or nitric oxide, or is a substratefor nitric oxide synthase. In yet another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, at least one therapeutic agent, and, optionally, at least onenitric oxide donor. The compounds can be administered separately or inthe form of a composition.

Another embodiment of the invention provides methods to decrease orreverse renal and other toxicities (such as, for example, kidneytoxicity, respiratory toxicity) by administering to a patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. For example, the patient can beadministered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one nitric oxide donor. In yet another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one therapeutic agent, and, optionally, at least one nitricoxide donor. The compounds can be administered separately or in the formof a composition.

Another embodiment of the invention provides methods to treat or preventdisorders resulting from elevated levels of COX-2 by administering to apatient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. For example, the patientcan be administered a therapeutically effective amount of at least oneCOX-2 selective inhibitor, that is optionally nitrosated and/ornitrosylated, of the invention. In another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and at least one therapeutic agent, including butnot limited to, steroids, a nonsterodal anti-inflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

Disorders resulting from elevated levels of COX-2 (e.g., COX-2 mediateddisorders) include, but are not limited to, for example, angiogenisis,arthritis, asthma, bronchitis, menstrual cramps, premature labor,tendinitis, bursitis; skin-related conditions, such as, for example,psoriasis, eczema, surface wounds, burns and dermatitis; post-operativeinflammation including from ophthalmic surgery, such as, for example,cataract surgery and refractive surgery, and the like; treatment ofneoplasia, such as, for example, brain cancer, bone cancer, epithelialcell-derived neoplasia (epithelial carcinoma), such as, for example,basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, such as,for example, lip cancer, mouth cancer, esophageal cancer, small bowelcancer and stomach cancer, colon cancer, liver cancer, bladder cancer,pancreas cancer, ovary cancer, cervical cancer, lung cancer, breastcancer and skin cancer, such as squamus cell and basal cell cancers,prostate cancer, renal cell carcinoma, and other known cancers thateffect epithelial cells throughout the body, benign and canceroustumors, growths, polyps, adenomatous polyps, including, but not limitedto, familial adenomatous polyposis, fibrosis resulting from radiationtherapy, and the like; treatment of inflammatory processes in diseases,such as, for example, vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury, myocardial ischemia, and the like; treatment ofophthalmic diseases and disorders, such as, for example, retinitis,retinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, glaucoma, inflammation of the eye and elevation of intraocularpressure and the like; treatment of pulmonary inflammation, such as, forexample, those associated with viral infections and cystic fibrosis, andthe like; treatment of central nervous system disorders, such as, forexample, cortical dementias including Alzheimer's disease, vasculardementia, multi-infarct dementia, presenile dementia, alcoholicdementia, senile dementia, and central nervous system damage resultingfrom stroke, ischemia and trauma, and the like; treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis; treatment of inflammations and/or microbial infectionsincluding, for example, inflammations and/or infections of the eyes,ears, nose, throat, and/or skin; treatment and/or prevention ofcardiovascular disorders, such as, for example, coronary artery disease,aneurysm, arteriosclerosis, atherosclerosis, including, but not limitedto, cardiac transplant atherosclerosis, myocardial infaraction,hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosis,thromboembolism, thrombotic occlusion and reclusion, restenosis, angina,unstable angina, shock, heart failure, coronary plaque inflammation,bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation, viral induced inflammation, inflammation associated withsurgical procedures, such as, for example, vascular grafting, coronaryartery bypass surgery, revascularization procedures, such as, forexample, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;treatment and/or prevention of urinary and/or urological disorders, suchas, for example, incontinence and the like; treatment and/or preventionof endothelial dysfunctions, such as, for example, diseases accompanyingthese dysfunctions, endothelial damage from hypercholesterolemia,endothelial damage from hypoxia, endothelial damage from mechanical andchemical noxae, especially during and after drug, and mechanicalreopening of stenosed vessels, for example, following percutaneoustransluminal angiography (PTA) and percuntaneous transluminal coronaryangiography (PTCA), endothelial damage in postinfarction phase,endothelium-mediated reocculusion following bypass surgery, blood supplydistrubances in peripheral arteries, as well as, cardiovasculardiseases, and the like; disorders treated by the preservation of organsand tissues, such as, for example, for organ transplants, and the like;disorders treated by the inhibition and/or prevention of activation,adhesion and infiltration of neutrophils at the site of inflammation;and disorders treated by the inhibition and/or prevention of plateletaggregation. The compounds and compositions of the invention can also beused as a pre-anesthetic medication in emergency operations to reducethe danger of aspiration of acidic gastric contents.

Another embodiment of the invention provides methods for improving thecardiovascular profile of COX-2 selective inhibitors by administering toa patient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. For example, the patientcan be administered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one nitric oxide donor. In yet another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,at least one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, antiplatelet agents, thrombin inhibitors, thromboxaneinhibitors, and, optionally, at least one nitric oxide donor. Thecompounds can be administered separately or in the form of acomposition.

When administered separately, the COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, can be administered about thesame time as part of the overall treatment regimen i.e., as acombination therapy. “About the same time” includes administering theCOX-2 selective inhibitor, that is optionally nitrosated and/ornitrosylated, simultaneously, sequentially, at the same time, atdifferent times on the same day, or on different days, as long as theyare administered as part of an overall treatment regimen, i.e.,combination therapy or a therapeutic cocktail.

When administered in vivo, the compounds and compositions of theinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the invention are administered as a combination ofat least one COX-2 selective inhibitor and/or at least one nitrosatedand/or nitrosylated COX-2 selective inhibitor and/or at least one nitricoxide donor and/or therapeutic agent, they can also be used incombination with one or more additional compounds which are known to beeffective against the specific disease state targeted for treatment. Thenitric oxide donors, therapeutic agents and/or other additionalcompounds can be administered simultaneously with, subsequently to, orprior to administration of the COX-2 selective inhibitor and/ornitrosated and/or nitrosylated COX-2 selective inhibitor.

The compounds and compositions of the invention can be administered byany available and effective delivery system including, but not limitedto, orally, bucally, parenterally, by inhalation spray, by topicalapplication, by injection, transdermally, or rectally (e.g., by the useof suppositories) in dosage unit formulations containing conventionalnontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles,as desired. Parenteral includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of theinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention, such as for treating pediatric fever andthe like, can be prepared by mixing the compounds or compositions with asuitable nonirritating excipient such as cocoa butter and polyethyleneglycols which are solid at room temperature but liquid at rectaltemperature, such that they will melt in the rectum and release thedrug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, surfactants, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered as asingle unit or in a sustained release form.

The bioavailabilty of the compositions can be enhanced by micronizationof the formulations using conventional techniques such as grinding,milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

The preferred methods of administration of the COX-2 selectiveinhibitors and compositions for the treatment of gastrointestinaldisorders are orally, bucally or by inhalation. The preferred methods ofadministration for the treatment of inflammation and microbialinfections are orally, bucally, topically, transdermally or byinhalation.

The compounds and compositions of the invention can be formulated aspharmaceutically acceptable salt forms. Pharmaceutically acceptablesalts include, for example, alkali metal salts and addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesuifonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitablepharmaceutically-acceptable base addition salts include, but are notlimited to, metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromprimary, secondary and tertiary amines, cyclic amines,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine and thelike. All of these salts may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

While individual needs may vary, determination of optimal ranges foreffective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

The amount of a given COX-2 selective inhibitor of the invention thatwill be effective in the treatment of a particular disorder or conditionwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques, including reference toGoodman and Gilman, supra; The Physician's Desk Reference, MedicalEconomics Company, Inc., Oradell, N.J., 1995; and Drug Facts andComparisons, Inc., St. Louis, Mo., 1993. The precise dose to be used inthe formulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided by thephysician and the patient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of theCOX-2 selective inhibitor. The usual daily doses of the COX-2 selectiveinhibitors are about 0.001 mg to about 140 mg/kg of body weight per day,preferably 0.005 mg to 30 mg/kg per day, or alternatively about 0.5 mgto about 7 g per patient per day. For example, inflammations may beeffectively treated by the administration of from about 0.01 mg to 50 mgof the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day. The compounds may beadministered on a regimen of up to 6 times per day, preferably 1 to 4times per day, and most preferably once per day. Effective doses may beextrapolated from dose-response curves derived from in vitro or animalmodel test systems and are in the same ranges or less than as describedfor the commercially available compounds in the Physician's DeskReference, supra.

The invention also provides pharmaceutical kits comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the invention,including, at least, one or more of the novel COX-2 selectiveinhibitors, that is optionally nitrosated and/or nitrosylated, and oneor more of the NO donors described herein. Associated with such kits canbe additional therapeutic agents or compositions (e.g., steroids,NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists and leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMG-CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like), devices for administering the compositions,and notices in the form prescribed by a governmental agency regulatingthe manufacture, use or sale of pharmaceuticals or biological productswhich reflects approval by the agency of manufacture, use or sale forhumans.

1. A compound selected from the group consisting of2-(2-(nitroxy)ethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-(2-(nitroxy)ethoxy)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,3-((nitroxy)methylphenyl)2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,6-(nitroxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-((2-(nitroxy)ethyl)sulfonyl) ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate and2-(4-(2-nitrooxyl)ethyl) piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, or apharmaceutically acceptable salt thereof.
 2. A composition comprising atleast one compound of claim 1 and a pharmaceutically acceptable carrier.